Structural characterization and comparative analysis of two crystalline forms of drug cocrystal (S086) by MicroED, XPS, and XAFS

Similar to the world’s first marketed ARNI drug sacubitril/valsartan (LCZ696), S086 is also a drug-drug cocrystal formed by neprilysin inhibitor (NEP) and angiotensin receptor blocker (ARB). ARNI drugs have played an important role in treating hypertension as a new class of antihypertensive drugs. Therefore, understanding the solid-state structure of S086 has become very meaningful. Employing advanced analytical techniques such as MicroED, XPS and XAFS, our comprehensive analysis has elucidated that the two crystalline forms, α and ξ of S086, are cocrystals derived from the synergistic combination of EXP3174, sacubitril, and calcium atoms, mediated by strong interactions. Due to the difficulty in obtaining X-ray single crystal structures, XPS and XAFS analyses, which offer unique insights into material structure, reasonably suggest that the two crystal forms of S086 possess highly similar coordination structures centered around calcium atoms with mixed ligands, but there are still subtle differences. The subtle differences in carboxylate coordination modes between α and ξ are reflected in the recently published linear and nonlinear IR spectroscopic studies of S086.